Microparticulate pharmaceutical delivery system

ABSTRACT

A pharmaceutical composition comprising a shaped enteric material having distributed therethrough preferably substantially uniformly, pharmaceutical loaded particles, said particles having a size no greater than about 10 microns in any dimension and being alkali insoluble and the method of delivering pharmaceuticals to Peyer&#39;s glands.

This application is a division of application Ser. No. 08/036,633, filedMar. 24, 1993, now U.S. Pat. No. 5,382,435.

BACKGROUND OF THE INVENTION

The present invention relates to a microparticulate pharmaceuticaldelivery system which is capable of ensuring that the pharmaceutical tobe delivered can be directed to be absorbed in the Peyer's glands of thesmall intestine.

There are a number of enteric coatings which are utilized to ensure thatacid labile pharmaceuticals or other materials can get safely by theacidic pH conditions in the stomach when ingested orally and which aredissolved in the alkaline pH conditions of the intestine and absorbedtherein. However, there are many drugs in which it is desired to avoidexposure to both the acidic conditions of the stomach and the akalineconditions of the intestine and yet be absorbed in the intestine so theycan be given in oral dosage form. Many pharmaceuticals are labile,inactivated or in same manner have their effectiveness limited in wholeor in part, under the pH conditions existing in the stomach andintestine.

It is known that the small intestine comprises three main sections, theduodenum, jejunum, and the ileum. Located primarily in the ileum arePeyer's glands, often referred to as "Peyer's patches", which containphagocytic cells which act to capture solid particles of ten microns orless that come into the intestine. This is important since particlescannot otherwise pass through the intestinal lining.

Some Peyer's glands exist in the jejunum particularly in the lowerportion thereof as one comes to the ileum, but they are few in numberand most are located in the ileum. Occasionally, and rarely, some areseen in the duodenum.

Heretofore, a satisfactory procedure to give oral doses ofpharmaceuticals for delivery to the Peyer's patch that are acid andakali labile has not been available.

SUMMARY OF THE INVENTION

The present invention overcomes the deficiencies of orally administeredacid and akali labile pharmaceutical compositions and provides an orallyadministered product which can be readily adsorbed only in the Peyer'sglands present in the small intestine.

Briefly stated, the present invention comprises a pharmaceuticalcomposition comprising a shaped enteric material having distributedsubstantially uniformly therethrough pharmaceutical-loaded particles,said particles having a size no greater than about 10 microns in anydimension and being alkali insoluble and the method of deliveringpharmaceuticals to Peyer's glands.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a pharmaceutical composition in accord with the instantinvention in the form of beads containing pharmaceutical-loadedmicroparticles.

FIG. 2 is a graph depicting the dissolution pH response of apharmaceutical composition in accord with the present invention.

DETAILED DISCUSSION

It will be seen that the two essentials of the instant invention are ashaped enteric material and the pharmaceutical-loaded particlesdistributed therethrough.

As used therein the phrase "shaped enteric material" means any materialknown to those in the pharmaceutical art to be able to resistdissolution under the acidic conditions present in the stomach and yetbe dissolved in the alkaline conditions that prevail in the smallintestine. These materials are well known and include alginates,alkali-soluble acrylic resins (EUDRAGITS®), cellulose acetate phthalate,hydroxypropyl methylcellulose phthalate, and the like. The term "shaped"as part of the expression simply means that the material can be in theform of beads or other shapes commonly used in forming pharmaceuticalcompositions. The size of the shaped enteric material is not critical,but, ordinarily for ease of ingestion they should be the smallest sizepossible ensuring that they will safely conduct the pharameutical-loadedparticles therein through the stomach and into the intestine. It hasbeen found that it is desired to primarily have beads of approximately 2mm to 6 mm in size, preferably around 4 millimeters is diameter. Theindividual shaped material, such as beads, can be incorporated intoconventional gelatin capsules or other like means for oral use. Thebeads, loaded with the particles can also be included in suitableconventional pharmaceutically-acceptable liquid. bases for oraladministration.

With respect to the pharamceutical-loaded particles, they are composedof an alkali insoluble encapulating substance and the activepharmaceutical itself and are 10 microns or less in size. The term"particles" as used in this invention is meant to include nanocapsules,microcapsules, nanospheres, microspheres, liposomes, and the like, inwhich the particles can be made of a cellulosic material such asethylcellulose, a polylactide, a polylactide-co-glycolide, orpolycaprolactone, a liposome, an emulsified oil or fat, a gelatin,albumin, an acrylic resin, and the like, all conventional and well knownalkali-insoluble encapsulating materials.

As to the pharmaceutical loaded in the particles there can be used anyacid and alkali labile products such as peptides, proteins, syntheticdrugs, oral vaccines, and the like, although the instant composition isespecially well suited for biotechnology recombinant protein productsand oral vaccines which require protection not only in the stomach, butalso in the intestinal tract.

It is important that in the production of the pharmaceuticalcompositions of the instant invention that no heat be utilized since thesame can have a deleterious effect on the pharmaceuticals noted,especially on the fragile recombinant products such as the proteinproducts and the oral vaccines.

It will be evident that the amount of active pharmaceutical in theparticles can vary greatly, dependent mainly on the dosage desired to begiven. For any given composition the proper dosage amount is determinedby including the requisite number of particles in the composition formedby admixing the particles with the shaped enteric material and includingthe proper amount of the composition in the oral medicament; e.g.gelatin capsule.

The preparation of the pharmaceutical composition of the instantinvention will be described in conjunction with the preferred shapedenteric material, namely an alginic acid.

What first transpires is the preparation of the particles in the form ofnanocapsules, microcapsules, nanospheres, and the like, and thesecapsules can be prepared by any conventional encapsulation process,preferably one that does not utilize any heat. Conventionalencapsulation processes such as solvent evaporation, coacervation/phaseseparation, emulsion polymerization, emulsion extraction, and aerosolgeneration can be used to prepare the small drug-loaded particles. Theparticulars (apparatus, and the like) of these processes are known tothose experienced in the art of microencapsulation and need no furtherelaboration here. Any process than can be used to prepare capsules lessthan 10 microns, preferably without the use of heat, can be used toprepare the small particles. The encapsulation is carried out to ensurethat the resultant particles are no more than about 10 microns indiameter.

The pharmaceutical-loaded particles are then dispersed into a solutionof sodium alginate in water and the beads form simply by adding themixture dropwise to an acidic solution, such as citric acid, which willimmediately insolubilize the sodium alginate drop into the shape of abead. The beads thus formed can be removed from the solution and drieduntil used. The beads will remain intact under ambient conditions andwhen administered for ingestion they remain intact at the pH encountedin the stomach. The alginic acid beads release the pharmaceutical-loadedparticles in the intestinal tract for absorption by the phagocytic cellsof the Peyer's glands.

Reference to FIG. 1 of the drawing shows such a bead 10 comprising theenteric shaped material 11, (alginic acid) having dispersed uniformlytherethrough the pharmaceutical-loaded particles 12 having a variety ofparticle sizes, if desired, but in any event none greater than 10microns in diameter. It will be understood that in those situationswhere it is desired to have in the same bead or other shaped entericmaterial not only a pharmaceutical to be delivered to the Peyer'sglands, but also any pharmaceutical(s) not alkali labile in theintestinal tract can be incorporated in the alginate and can be of adiameter larger than 10 microns. It will be also evident that differentshaped particles and particles loaded with different pharmaceuticals canbe incorporated in the same bead.

FIG. 2 is a graph depicting the time, in minutes, within which 100% ofthe enteric material will be dissolved at various pH levels. It showsthe almost instantaneous dissolution at pH 8 which would leave theparticles free to be absorbed by the phagocytic cells in the Peyer'sglands.

The invention will be further described in connection with the followingexample which is set forth for purposes of illustration only.

EXAMPLE

Albumin, to simulate a pharmaceutical agent, was encapsulated withpolylactide-co-glycolide utilizing a solvent evaporation process thatdid not involve heating to form microcapsules no greater than 10 micronsin diameter. The prepared microcapsules were substantially uniformlydispersed into a solution prepared by dissolving sodium alginate indeionized water.

Beads of the mixture were formed by adding the mixture dropwise to anaqueous citric acid solution. The result is that the alginic acidinsolubilizes forming beads containing the pharmaceutical-loadedparticles dispersed substantially uniformly therethrough.

Beads of approximately 4 mm in diameter were prepared.

In order to determine the dissolution profile, beads were exposed tobuffers at various pHs giving the following dissolution profile:

pH 2: No release at 12 hours

pH 3: No release at 12 hours

pH 4: Approx. 10% release at 12 hours

pH 5: 100% at 12 hours

pH 6: 100% at 105 minutes

pH 7: 100% at 65 minutes

pH 8: 100% at 50 minutes

It will be evident that in place of the sodium alginate otherconventional enteric materials as discussed above may be utilized andequally any pharmaceuticals can be utilized. What is critical, however,is that the pharmaceutical loaded-particles, preferably in the shape ofa microcapsule or microsphere, be no larger than about 10 microns indiameter and that the encapsulating material be alkali-insoluble.

While the invention has been described in connection with a preferredembodiment, it is not intended to limit the scope of the invention tothe particular form set forth, but on the contrary, it is intended tocover such alternatives, modifications, and equivalents as may beincluded within the spirit and scope of the invention as defined by theappended claims.

What is claimed is:
 1. The method of delivering a pharmaceutical to beabsorbed in Peyer's glands comprising loading said pharmaceutical intoan alkali-insoluble particle having a maximum size in any dimension nogreater than about 10 microns, incorporating said particle in a shapedenteric material, and administering said material.
 2. The method ofclaim 1 wherein the enteric material is an alginate, alkali-solubleacrylic resin, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, or mixtures thereof.
 3. The method of claim 2wherein the particle containing the pharmaceutical is made of analkali-insoluble cellulosic material, a polylactide, apolylactide-co-glycolide, a polycaprolactone, a liposome, an emulsifiedoil or fat, a gelatin, an albumin, an acrylic resin, or mixturesthereof.
 4. The method of claim 3 wherein the shaped enteric material isin the form of a bead having a diameter of about 2 to 6 mm.
 5. Themethod of claim 4 wherein the enteric material is an alginate and theparticles are made of ethylcellulose.
 6. The method of claim 5 whereinthe particles are in the form of nanocapsules, microcapsules,nanospheres, microspheres, liposomes, or mixtures thereof.